Squamous cell carcinoma (SCC), a highly metastatic lesion, accounts for approximately 96 percent of all oral cancers. Tumor metastasis requires multiple interactions with the extracellular matrix (ECM), including cell migration, invasion and matrix remodeling. Our group has shown that the ECM molecule tenascin-C (TN-C) and its integrin receptor, alphavbeta6, are neo-expressed in oral SCC. TN-C, a hexameric glycoprotein containing antiadhesive domains, reportedly promotes cell motility. The alphav integrin subfamily has also been reported to mediate cell motility. Coexpression of TN-C and alphavbeta6 thus provides a permissive environment for tumor cell invasion. Recently, others showed that a transmembrane molecule found on the surface of some tumor cells, extracellular matrix metalloproteinase inducer (EMMPRIN), stimulates matrix metalloproteinase (MMP) secretion by peritumor fibroblasts. Using human biopsy specimens, we observed an increase in staining for EMMPRIN in both oral dysplasia and oral SCC when compared with normal oral mucosa. We also identified a novel role for EMMPRIN as a modulator of TN-C matrix deposition. In the presence of antibodies to EMMPRIN, the deposition of TN-C matrices by cocultures of SCC cells and peritumor fibroblasts was inhibited, and their secretion of the latent forms of both MMP-2 and MMP-9 was increased. Anti-EMMPRIN antibodies also perturbed oral SCC cell motility in vitro. We hypothesize that TN-C, EMMPRIN, and alphavbeta6 influence oral cancer by acting as interdependent stimulatory modulators of tumor cell invasion and gene expression. Specific aims 1 and 2 were put forth in the funded R-29DE11930-02A grant and should be completed within the 5 years as originally proposed. The new specific aims (boldface) represent additional work to be done in years 6 and 7. The specific aims of this proposal are: (1) To determine whether alterations in the expression of alphavbeta6 will modify the invasive behavior of oral SCC cells. (2) To evaluate different stages of tumor invasion, using an animal model, for differential expression of TN-C and alphabeta6. (3) To investigate EMMPRIN's role in TN-C matrix deposition by determining the effects of anti-EMMPRIN antibodies on MMPs that may interact with TN-C. (4) To evaluate the effects of overexpressing EMMPRIN in poorly invasive oral SCC cells. These experiments should help us understand the mechanisms underlying ECM remodeling in oral cancer.